Palladium-catalyzed coupling of ortho-alkynylanilines with terminal alkynes under aerobic conditions: Efficient synthesis of 2,3-disubstituted 3-alkynylindoles

Article abstract of DOI:10.1002/anie.201205596

Two nucleophiles, one triple bond: Under aerobic conditions, palladium-catalyzed direct coupling of o-alkynylanilines and terminal alkynes took place smoothly to afford the 2,3-disubstituted 3-alkynylindoles 3 in good to excellent yields. The intermediate A was characterized and a retro-aminopalladation of B was observed for the first time. Copyright

Full text of DOI:10.1002/anie.201205596

Angewandte
Chemie
DOI: 10.1002/anie.201205596
Heterocycles
Palladium-Catalyzed Coupling of ortho-Alkynylanilines with Terminal
Alkynes Under Aerobic Conditions: Efficient Synthesis of
2,3-Disubstituted 3-Alkynylindoles**
Bo Yao, Qian Wang, and Jieping Zhu*
Dedicated to Professor Lutz F. Tietze on the occasion of his 70th birthday
The indole nucleus is an ubiquitous heterocycle found in
many bioactive natural products, pharmaceuticals, and agro-
chemicals.[1] The synthesis and functionalization of indoles
have attracted chemists for over a century and remain an
active research area.[2] In this context, transition-metal-
catalyzed transformations, notably the indole synthesis by
Cacchi and co-workers[3] and the heteroannulation by Larock
et al.,[4] among others,[5] have had a major impact on the field.
The 2- and 3-alkynylindoles are interesting synthetic
targets because of their potential biological activities[6] and
possibilities they can offer for further structural elaboration.[7]
To access these compounds, several metal-catalyzed trans-
Scheme 1. Alkynylation to 3-alkynylindoles. DMSO=dimethylsulfoxide.
formations have been developed, including a) the classic
Sonogashira coupling using halogenated indoles,[7] b) direct
À
C H functionalization of indoles with alkynylhalides (pseudo
halides)[8] or hypervalent iodine reagents,[9] and c) dehydro-
genative coupling of indoles and terminal alkynes.[10] While
these methods focused on the functionalization of the indole
ring,[11] the palladium(0)-catalyzed domino indolization/alky-
nylation of o-alkynylanilines in the presence of 1-bromo-
alkynes has also been developed by Cacchi et al. for the
synthesis of 2,3-disubstituted 3-alkynylindoles (Sche-
me 1a).[12] In general, the indole synthesis by Cacchi and co-
workers uses organic halides as electrophilic coupling part-
ners and is performed under inert atmosphere in the presence
of a phosphine ligand. We recently discovered that a nucleo-
phile such as an internal amide could act as an effective
reaction partner for o-alkynylaniline when the Cacchi cycli-
zation was carried out under oxidative conditions.[13] Herein,
we report that terminal alkynes can also enter into the
oxidative catalytic cycle with the o-alkynylaniline 1, and
document an unprecedented palladium(II)-catalyzed cou-
pling of 1 with the terminal alkynes 2 under mild aerobic
conditions for the synthesis of 2,3-disubstituted 3-alkynyl-
indoles (Scheme 1b).
By using N,N-dimethyl-ortho-(1-phenylethynyl)aniline
(1a)[14] and 4-ethynyltoluene (2a) as test substrates, the
optimum reaction conditions were found to involve perform-
ing the reaction in DMSO at 808C in the presence of
Pd(OAc)2 (0.05 equiv), nBu4NI (1.0 equiv), and HOAc
(1.0 equiv) in air (Table 1, entry 9). Under these reaction
conditions, the desired domino process occurred smoothly to
provide
1-methyl-2-phenyl-3-(p-tolylethynyl)-1H-indole
(3aa) in 88% yield upon isolation.[15] Some points deserve
additional comment: a) the presence of Cu(OAc)2 as a coca-
talyst was detrimental as it led to the formation of a significant
amount of 3,3’-bisindole[16] and 1,4-di-p-tolylbuta-1,3-diyne
resulting from the dimerization of 1a and oxidative dimeri-
zation of 2a,[17] respectively (entry 4); b) using 1.0 equivalent
of HOAc and nBu4NI each is optimum. In the presence of
2.0 equivalents of HOAc (entry 5), the reaction became more
complex, whereas with
a substoichiometric amount of
nBu4NI, the yield of 3aa was significantly reduced (entry 6
versus 7); c) higher concentration (c = 0.2; entry 10) and
higher reaction temperature (1008C; entry 11) under other-
wise identical reaction conditions afforded 3aa in a lower
yield.
[*] Dr. B. Yao, Dr. Q. Wang, Prof. Dr. J. Zhu
Ecole Polytechnique Fꢀdꢀrale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@epfl.ch
With the optimum reaction conditions in hand, the scope
of the reaction was next investigated. As expected, aromatic
substituents in both starting materials (R1, R2 = aromatic)
having different electronic properties were well tolerated and
the reaction between the diarylacetylenes 1 and arylethynes 2
gave 3-alkynylindoles in good to excellent yields (3aa–3af
and 3ba–3da; Scheme 2). The reaction conditions were
applicable to aliphatic alkynes (R1, R2 = alkyl) as well, and
various functionalities such as chlorine, hydroxy, benzyloxy,
Homepage: http://lspn.epfl.ch
[**] We thank the EPFL (Switzerland), Swiss National Science Founda-
tion (SNSF), and Swiss National Centres of Competence in
Research (NCCR) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205596.
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Table 1: Condition survey for the palladium-catalyzed coupling of 1a and
2a.[a]
Entry
PdII
nBu4NI
AcOH
2a
Yield [%][b]
(equiv)
(equiv)
(equiv)
(equiv)
1a
4a
3aa
1
2
3
0.025
0.025
0.025
0.025
0.025
0.05
0.05
0.05
0.05
0.05
0.1
0.3
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
2.0
2.0
2.0
36
23
6
28
0
0
0
0
–
4
31
39
54(41)
13
14
64
80 (72)
62
(88)
(65)
(74)
10
19
36
20
8
3
8
–
–
4[c]
5[d]
6[d]
7[d]
8[d]
9
10[e]
11[f]
–
–
0.05
–
[a] Reaction conditions: 1a (0.1 mmol), 2a, Pd(OAc)2, nBu4NI, and
AcOH in DMSO (1.0 mL) was heated at 808C under air atmosphere
(1 atm) for 24 h. [b] Yields were determined by 1H NMR spectroscopy
using CH2Br2 as an internal standard. The value within parentheses is
yield of the isolated 3aa. [c] Cu(OAc)2 (0.1 equiv) was added. [d] 36 h.
[e] 0.5 mL of DMSO was used. [f] Reaction was performed at 1008C.
and cyano groups were tolerated. Since the preparation of
unsymmetrical 2,3-dialkyl-substituted indoles represents a sig-
nificant synthetic challenge,[18] it was thus delightful to find
that the 2-alkyl-3-(1-alkylethynyl)indoles (3hj and 3hk; R1
and R2 = alkyl) could also be synthesized in good yields using
this method.[19,20] N-methyl-N-pentyl-ortho-(1-phenylethy-
nyl)aniline coupled effectively with 4-ethynyltoluene to
afford N-pentyl-2-phenyl-3-(p-tolylethynyl)-1H-indole (3ia)
in 50% yield.[21]
Two possible elementary steps could initiate the present
alkynylation process: a) formation of
a s-alkynylpalla-
dium(II) complex, b) the aminopalladation of o-alkynylani-
line leading to a s-indolylpalladium(II) intermediate. To gain
insight into the mechanism, a series of experiments have been
performed. Mixing 1c and Pd(OAc)2 (1.0 equiv) in
[D6]DMSO at room temperature rapidly produced a new
compound, whose structure was assigned as the s-indolylpal-
ladium(II) intermediate A on the basis of detailed spectro-
scopic studies [Eq. (1), Scheme 3; see the Supporting Infor-
mation]. To capitalize on the reactivity of this intermediate,
the following control experiments were carried out. Firstly,
addition of 4-ethynyltoluene (2a, 1.0 equiv) to a [D6]DMSO
solution of A produced a mixture of the cross-coupled
product 3ca and the starting material 1c [Eq. (2),
Scheme 3]. Since A was stable in the absence of the terminal
alkyne 2a, we assumed that 1c was produced by a retro-
aminopalladation of the s-indolyl-s-alkynylpalladium B,
which was generated in situ from A and 2a. Secondly,
addition of nBu4NI (4.0 equiv) to the solution of A produced
an unidentified complex [Eq. (3), Scheme 3]. Neither
Scheme 2. General conditions: a solution of 1 (0.1 mmol) and 2
(0.2 mmol) in DMSO (1.0 mL) was heated at 808C in the presence of
Pd(OAc)2 (0.05 equiv), nBu4NI (1.0 equiv), and HOAc (1.0 equiv)
under air atmosphere (1 atm) for 24 h.
1
AcOMe nor 1c were detectable by H NMR spectroscopy
of the crude reaction mixture, thus indicating that N-
demethylation and retro-aminopalladation did not take
place in this case. However, addition of 2a to the above
mixture generated 3ca as well as AcOMe which was detected
1
by H NMR spectroscopy. These control experiments indi-
cated that a) the s-indolylpalladium(II) complex A is a viable
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invoked as an intermediate in the paladium-catalyzed syn-
thesis of functionalized indoles, the retro-aminopalladation
has, to the best of our knowledge, never been unequivocally
identified previously.
The ability of a palladium complex of the type C to trigger
the indole formation has been amply demonstrated by Cacchi
and co-workers. In view of the observed facile aminopallada-
tion process and the fact that Pd(OAc)2 is more electron
deficient than the s-alkynylpalladium complex,[24] we think
that a catalytic cycle involving C may not be a predominant
one under our oxidative conditions. A more plausible
catalytic cycle was therefore proposed as shown in
Scheme 5. Pd(OAc)2-catalyzed intramolecular aminopallada-
tion of 1 led to the formation of the s-indolylpalladium
intermediate A. Coordination of A to the terminal alkyne 2
Scheme 3. Identification of a key intermediate and control experi-
ments. Neutral ligands on Pd were omitted for clarity.
intermediate on the way to 3ca, b) the intermediate B is
susceptible to retro-aminopalladation, presumably because of
a more pronounced trans effect of the alkynyl group,[22] and
thus could lead to a nonproductive pathway, c) B is more
susceptible than A towards N-demethylation which drove the
reaction toward the formation of the desired product, and
d) the present domino alkynylation went through a PdII/Pd0
catalytic cycle.
The retro-aminopalladation from B should produce the s-
alkynylpalladium complex C[23] in addition to 1c [Eq. (2),
Scheme 3]. As it was difficult to discern its presence by
1H NMR spectroscopy, an additional experiment was per-
formed to trap this reactive intermediate (Scheme 4). Addi-
tion of 2a to a solution of A and N,N-dimethyl-2-(4’-
methoxyphenylethynyl)aniline (1d) in [D6]DMSO afforded,
after 40 minutes at RT, the two 3-alkynylindoles 3ca and 3da
(ratio 5:1) in addition to the two anilines 1c and 1d. This
result indicated that B was a second possible intermediate in
our alkynylation process and that this intermediate readily
underwent the retro-aminopalladation process. While s-
indolyl-s-arylpalladium of type B has been frequently
Scheme 5. Palladium(II)-catalyzed alkynylation: a plausible reaction
pathway. Neutral ligands on Pd were omitted for clarity.
and subsequent deprotonation afforded the s-indolyl-s-
alkynylpalladium B, which underwent N-demethylation by
SN2 attack of iodide onto the indolium to furnish D and MeI.
Reductive elimination from D provided the product 3 and
Pd0. The oxidation of Pd0 to PdII by air completes the catalytic
cycle. Since iodide is regenerated under the reaction con-
ditions by its reaction with acetate, only a catalytic amount of
iodide is in principle needed. Although this is indeed the case,
the reduced efficiency (entry 3 versus 7, Table 1) implied that
a fast iodide-mediated N-demethylation (conversion of B into
D) is important to ensure the occurrence of the desired
domino process. Otherwise, B could undergo the retro-
aminopalladation, thus reducing the yield of 3. The fact that
dimerization of terminal alkynes was effectively minimized in
this domino process is also supportive of the proposed
mechanism as this pathway did not involve the formation of
a discrete s-alkynylpalladium(II) complex which is prone to
dimerization and degradation under oxidative conditions.
In conclusion, we have reported an efficient synthesis of
2,3-disubstituted 3-alkynylindoles by a novel palladium(II)-
catalyzed domino reaction[25] between two alkynes under
aerobic oxidative conditions. A s-indolylpalladium(II) com-
Scheme 4. Further evidence of retro-aminopalladation by a cross-over
experiment.
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transformation was illustrated. We also identified the N-
demethylation step that took place right after the formation
of the s-indolyl-s-alkynylpalladium intermediate (B). The
rapid N-demethylation of B by nBu4NI is important as it
prevents the occurrence of retro-aminopalladation of com-
plex B. The present domino reaction displayed broad
substrate scope, good functional group tolerance, and high
synthetic efficiency. The so-developed oxidative conditions
allow the use of nucleophiles (terminal alkynes) instead of
electrophiles (organic halides) as the reaction partners for o-
alkynylanilines, and are therefore complementary to indole
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Experimental Section
General procedure: A 5 mL vial was charged with 1a (0.1 mmol), 2a
(0.2 equiv), Pd(OAc)2 (5 mol%), nBu4NI (1.0 equiv), acetic acid
(1.0 equiv), and DMSO (1.0 mL). After being heating at 808C under
air (1 atm) for 24 h, the reaction mixture was quenched with water
and the aqueous phase was extracted with EtOAc. The combined
organic extracts were washed with brine, dried over sodium sulfate,
filtered, and concentrated in vacuo. The residue was purified by silica
gel column chromatography (petroleum ether/dichloromethane =
10:1) to give the product 3aa (28.3 mg, 88%) as a brown oil.
1H NMR (400 MHz, CDCl3): d = 7.90–7.85 (m, 1H), 7.73–7.68 (m,
2H), 7.58–7.51 (m, 2H), 7.50–7.44 (m, 1H), 7.41–7.24 (m, 5H), 7.12
(d, J = 7.8 Hz, 2H), 3.77 (s, 3H), 2.36 ppm (s, 3H); 13C NMR
(101 MHz, CDCl3): d = 143.7, 137.3, 131.1, 131.0, 130.4, 129.1, 128.9,
128.6, 128.5, 123.0, 121.6, 120.9, 120.2, 109.9, 97.1, 91.9, 83.5, 31.8,
21.6 ppm; ATR-IR n 3054 (w), 2918 (w), 2201 (w), 1489 (w), 1487 (m),
1468 (m), 1367 (m), 1264 (m), 816 (s), 741 (s), 699 (s); HRMS (ESI)
calcd for C24H20N+ [M+H]+ 322.1590; found 322.1581.
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Received: July 14, 2012
Revised: August 27, 2012
Published online: November 4, 2012
Keywords: heterocycles · homogeneous catalysis · oxidation ·
.
palladium · synthetic methods
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[20] Hydrogenation of 3ga under standard conditions (Pd/C, MeOH,
1 atm H2) afforded the 2,3-dialkylated indole; see the Support-
ing Information.
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methyl 3-unsubstituted indoles (65%, 64%, 48%, respectively).
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these substrates. The N,N-dibenzyl derivative gave the corre-
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reaction occurred when the N-methyl-N-phenyl derivative was
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1
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